Amyloidosis is a condition which is characterized by the deposition of amyloid in organs or tissues of the human or animal body, either as a primary disease or unknown cause or secondary to chronic disease, such as tuberculosis or osteomyelitis. In addition, it has also be found that the pre-eminent neuropathological feature of Alzheimer's disease (AD), a chronic condition of brain atrophy, is the deposition of amyloid in the brain parenchyma and cerebrovasculature (D. J. Selkoe, Neuron 6, 487-498 (1991); D. J. Selkoe, Annu. Rev. Cell Biol. 10, 373-403 (1994)).
The basic component of such amyloid is a peptide termed amyloid .beta., or A.beta. (G. C. Glenner, C. W. Wong, Biochem. Biophys. Res. Commun. 120, 885-890 (1984)). It is a 40 to 42 amino acids long proteolytic fragment of the Alzheimer amyloid precursor protein (APP), a protein expressed in most tissues (J. Kang, et al., Nature 325, 733-736 (1987)). Genetic and neuropathological studies provide strong evidence for a central role of A.beta. in the pathogenesis of AD, but the pathophysiological consequences of the amyloid deposition are still unclear. However, it has been suggested that A.beta. polymers and amyloid are toxic to neurons, either directly or indirectly, and hence cause neurodegeneration (C. Behl, J. B. Davis, R. Lesley, D. Schubert, Cell 77, 817-827 (1994); D. T. Loo, et al., ibid 90, 7951-7955 (1995)).
The amyloid associated with Alzheimer's disease (AD) consists of thin fibrils of polymerized A.beta.. A rational pharmacological approach for the prevention of amyloidogenesis would therefore be to use drugs that specifically interfere with A.beta.--A.beta. interaction and polymerization. Previous studies showed that A.beta. polymerization in vivo and in vitro is a highly specific process, which probably involves an interaction between binding sequences in the A.beta. peptide (J. Naslund, et al., Proc. Natl. Acad. Sci. USA 91, 8378-8382 (1994); J. Naslund, et al., Biochem. Biophys. Res. Commun. 204, 780-787 (1994)).
Wood et al (S. J. Wood, R. Wetzel, J. D. Martin, M. R. Hurle, Biochemistry 34, 724-730 (1995)) suggest that amino acid residues within or close to A.beta.-16-20 are important for the adoption of the correct .beta.-pleated sheet structure of A.beta. and show that amino acids 17-23 in the amyloid .beta. peptide (A.beta.) are essential for fibril formation and probably make up the .beta.-sheet core of the fibrils. In addition, Wood et al. have investigated the ability of their peptides to form amyloid fibrils in a solution containing solely the mutated or the wild-type peptide. However, no method or principle which makes it possible to inhibit A.beta. of wild type from forming amyloid fibrils is devised and no use of the peptides as medicaments is suggested.
WO 95/08999 relates to amelioration of amnesia in Alzheimer's disease caused by deposition of amyloid .beta. protein. Three peptides are disclosed, which overcome the amnestic effects of .beta.-12-28, a peptide homologous to A.beta.. In addition, WO 95/08999 describes the screening of several other peptides, which were neither significantly amnestic nor memory enhancing, of which one is KLVFF, SEQ. NO. 15 of the sequence listing therein.
In EP 0 584 452, novel amyloid precursor proteins and the sequences thereof are disclosed. Peptide sequences that comprise KLVFF are revealed. However, neither binding to amyloid .beta. peptide nor any inhibition of the polymerization thereof is suggested.